I am committed to an academic career in the basic science of bone biology with a focus on the mechanisms by which mechanical signals regulate bone homeostasis. My long-term goal is to become a leader at the VA in the field of bone biology. I have a strong background in models of mechanotransduction and have gained experience during my postdoctoral training in the characterization of genetically-altered mice. In this Career Development Award Application, I will apply these two aspects of my scientific background to examine the role of Wnt/2-catenin signaling in the response of bone to mechanical loads. 2-catenin is activated by mechanical signals both in vivo and in vitro, but the mechanism by which this transcription factor is activated remains unclear. Specific Aim 1 will determine the role of the Wnt co-receptors Lrp5 and Lrp6 in mediating the activation of 2-catenin and bone formation after mechanical loading. We will then examine mechanisms by which 2-catenin activity is regulated. Preliminary date suggests that the expression of hypoxia-inducible factor-11 is increased by mechanical signals and that this factor may act to inhibit 2-catenin activity. Specific aim 2 will characterize the effect of skeletal specific-deletion of Hif-11 on load induced osteogenesis and Wnt/2-catenin signaling. Each specific aim utilizes a combination of in vitro and in vivo studies to determine the roles of these factors in bone cell mechanotransduction. It is my strong belief that the completion of this work will provide new insights into the mechanisms by which physical stimuli regulate bone mass and lead to the development of novel therapeutic strategies designed to improve bone strength in veterans. Further, the results of these studies will form the basis for a larger Merit Review grant, and when combined with the mentorship provided by Dr. Clemens and Dr. Semenza and additional training in laboratory management, grantsmanship, and scientific presentation should ensure my success as an independent VA investigator. PUBLIC HEALTH RELEVANCE: Veterans who have suffered traumatic injuries that limit mobility have an increased risk of developing osteopenia. While most osteoporosis treatments increase bone strength by inhibiting bone resorption, mechanical signals reduce bone resorption while also increasing bone formation. Understanding the cellular and molecular mechanisms by which mechanical signals increase skeletal mass and strength may lead to the development of new therapies that reduce fracture risk. Our work will identify new mechanisms controlling the anabolic response of bone to mechanical loads by examining the interaction of the Wnt/2-catenin pathway and the hypoxia-inducible factor pathway.